In the spring of 2003, an outbreak of unknown etiology began in South East Asia and quickly spread to several other countries. The disease, termed severe acute respiratory distress syndrome or SARS, was identified and contained by a massive public health effort orchestrated by the WHO and local authorities. The etiological agent of this disease was identified as a new strain of coronavirus, and given the name SARS-CoV. In order to gain additional knowledge as to the replication, pathogenesis and immune responses induced by the virus, animal and cell culture models are needed. The experiments described in this application are aimed at establishing 1) in vitro tissue culture models for SARS-CoV infection using primary respiratory epithelial cells 2) a mouse model for SARS-CoV infection using wild type as well as immunodeficient mouse strains and 3) structure/function analysis systems for SARS-CoV ORFs of unknown function. Successful completion of the aims outlined in this application will establish systems for investigating the cell biology and pathogenesis of SARS-CoV.